FR2686515A1 - Use of niobium derivatives as active principle of medicaments which are useful in the treatment and/or prevention of disorders of carbohydrate and/or lipid metabolism - Google Patents

Abstract

The invention relates to a novel use of derivatives of niobium in the oxidation state 4 or 5, as active principle for the manufacture of medicaments which are useful in the treatment and/or prevention of disorders of carbohydrate and/or lipid metabolism. The niobium derivatives which are useful according to the invention are in the form of inorganic salts or of organometallic salts or complexes. The medicaments are useful for the treatment of diabetes, hypercholesterolaemia, hyperlipidaemia, hypertriglyceridaemia and complications associated with these pathologies.

Description

Use of niobium derivatives as active principle of medicaments useful in the treatment and / or prevention of disorders of the metabolism of carbohydrates and / or lipids.

 The present invention relates to the use of niobium derivatives as active principle of medicaments useful in the treatment and / or prevention of disorders of the metabolism of carbohydrates and / or of lipids.

 The search for new hypoglycemic derivatives for the treatment of diabetes is very important because, in the current state, the available substances (insulin, biguanides, chlofibrates, sulfonamides, etc.) help to control it via a regulation of the blood sugar, treat the "effects" of diabetes and the metabolic disorders associated with it, but do not treat the causes most of which are unknown and do not treat it. In addition, these treatments are long-lasting, generally for life, and restrictive for the individual (daily injections). They are therefore necessarily accompanied by side effects and new pathologies appear over the years (insulin resistance, blindness, etc.).

With the discovery and study for several years of essential trace elements, certain metal ions have been described as having insulin-magnetic properties. This is particularly the case for the mineral salts of vanadium as can be seen from the bibliographic update entitled "The bioinorganic Chemistry of Vanadium" carried out recently by Dieter
REHDER (Angew. Chem. Int. Ed. Engl. 1991, 30, 148-167) of certain derivatives of molybdenum and others of chromium (in particular a natural peptide not yet fully identified (called GTF, and a derivative baptized dithiochrome , cf. WO 91/01738, published on February 21, 1991. In addition, numerous metalloenzymes have been discovered involving V, Cr or Mo naturally, or as a replacement for another missing or deficient metal.

 the current hypothesis is that metal ions such as vanadate have an important biological action by analogy with phosphate ions, in particular because they have substantially the same size and the same lengths of metal-oxygen bonds.

 Much work has been done on the activity of vanadium in the treatment of hyperglycemia. These are mainly scientific literature documents which deal only with mineral derivatives of vanadium.

In the literature since 1985, numerous studies describe the hypoglycemic effects of mineral derivatives of vanadate (+5) or vanadyle (+4) ions. An excellent bibliographical update can be found in the Doctoral Thesis in Pharmacy of
Jean-Jacques MONGOLD, September 1991, University of Montpellier I,
France.

 European patent EP-O 264 278 describes compositions with insulin-mimetic activity containing vanadates and mineral peroxovanadates.

 Furthermore, the applicant has described in its international applications WO 91/07406 and WO 91/13892 as well as in its French application not yet published and filed on May 21, 1991 under the number 91 06 174 organo-metallic complexes of transition metals porphyrinic structure useful in particular in the treatment of hyperglycemia.

 European patent EP-O 305 264 describes organomineral vanadyl compounds obtained from C6-C10 esters of cysteine.

 Japanese patent JP 2 292 217 describes an antidiabetic activity for 7 vanadyle-dioxo complexes (tartrate, gluconate, malonate, oxalate, lactate, salycilate and acetyl-acetonate), as well as for 2 vanadyle-monoamino-monothio complexes: the l complex 'methyl ester of cysteine with vanadyl and that of 2-amino-ethane-thiol.

 Mineral salts of niobium as well as some organic derivatives of niobium (cyclopentadienyls and isothiocyanates) have other medical uses (toothpaste, contrast agent for radiography or NMR imaging, or use in oncology).

They are therefore administered to humans and their toxicity is known. For example, the Merck Index, Il Edition, reports that oxovanadate chloride (VOICI3 product No. 9834) has an oral lethal dose LD50 = 140 mg / kg for rats (which makes 41.2 mg of metal / kg) , while niobium chloride (NbCl5 product no. 6473) has an oral lethal dose LD50 = 830 mg / kg for mice (which makes 285 mg of metal / kg). It would therefore seem that niobium has a lower toxicity than vanadium, which itself is much less toxic than chromium VI.

The synthesis of niobium derivatives or complexes is well known: for example it can be done according to the methods listed by Leopold Gmelins, and described in: Handbuch der anorganischen Chemie, 8 Auflage, Niobium (System Nummer 49),
Teil B4, Verbindungen, VerlagChemie-GMBH, Weinheim / Bergstrasse, 1973, in particular on pages 334-472 for organic complexes. The mineral salts of niobium can be prepared according to known procedures described for example in the above book, niobium sulfates on page 303.

Niobium alkoxides, niobium dialkylamides and niobium aminoalkoxides can also be prepared by following, for example, the procedures described in the patents
EP O 450 717 and EP 0 442 563.

Niobium complexes with hydroxy acids (such as tartaric, lactic, glycolic and malic acids) can be prepared by following, for example, the procedures described by
E. RUZDIC and N. BRNICEVIC in Inorganica Chimica Acta, 1984, 88, 99-103.

 Peroxo niobium complexes with organic derivatives such as tartaric, lactic, glycolic, dipicolinic and malic acids can be prepared by following for example the procedures described by A.C. Dengel and W.P. Griffith, Polyhedron, 1989, 8, 1371-1377.

 At present, niobium is not considered to be an essential trace element and is not used for the prevention or treatment of disorders of carbohydrate and / or lipid metabolism.

 Furthermore, the analogy with phosphate ions which can be made, as we saw above in the case of vanadium, is by no means justified in the case of niobium.

 Therefore, nothing made it obvious that niobium would exhibit a therapeutic activity similar to that of vanadium in the treatment of diabetes and associated diseases.

 Now, the Applicant has now discovered that niobium derivatives with a degree of oxidation 4 or 5 have an activity comparable to that of vanadyle and vanadate in the treatment of diabetes and more broadly prove to be active for treatment and prevention carbohydrate and / or lipid metabolism disorders and complications associated with these pathologies.

 The Applicant has discovered that this activity could be further significantly increased by complexation of said derivatives with different organic ligands.

Generally speaking, the term “complex according to the invention” will be understood to mean the reaction product of a niobium derivative with oxidation state 4 or 5 with an organic ligand. They are, in general, mixtures of complexes corresponding to the fixing by bonds with 1 and / or 2 electrons of a variable number of heteroatoms according to the ligand used whose spatial arrangement around the metal and the degree of coordination metal may vary
Since the above complexes have the particularity of being formed very easily by contact, either in solution or in suspension, of a niobium derivative at oxidation state 4 or 5 with an organic ligand, the invention covers not only the use of said complexes already formed as active ingredient for the manufacture of a medicament useful in the treatment and prevention of disorders of the metabolism of carbohydrates and / or lipids, but also the use of the mixture of the two types of constituents (derived from niobium at oxidation state 4 or 5 and organic ligand), the complexation of which will be carried out in vivo during the administration of the pharmaceutical composition.

 The term “association” denotes both the mixture of the two types of constituents and the product of the complexation reaction.

 Thus, according to an essential characteristic, the present invention relates to a new use of niobium derivatives in the oxidation state 4 or 5 as active ingredient for obtaining a medicament useful in the treatment of disorders of the metabolism of carbohydrates and / or lipids. .

 Among the diseases whose treatment or prevention is particularly targeted in the context of the present invention, mention will first of all be made of diabetes but also hypercholesterolemia, hyperglyceridemia, hyperlipidemia as well as the diseases associated with these pathologies.

 Examples of associated pathologies include arterial hypertension, arteriosclerosis, heart failure, peripheral ischemia or ocular pathologies progressing to blindness.

 According to a first variant of the invention, the niobium is in the form of an inorganic derivative.

 Advantageously, this mineral derivative is soluble in water.

 One will preferably choose from these salts, salts giving solutions of pH between 3 and 9, preferably close to normality.

 Examples of mineral derivatives which can be used include oxides, sulfates, halides, hydrochlorides, metallates of alkali or ammonium salts, as well as their hydrates or their complexes with a solvent.

 By way of oxide, particular mention will be made of Nib205.

 As chloride, mention will be made of NbCl4 and NbC15.

 Among the preferred sulphates, mention will be made most particularly of that corresponding to the formula (NH4) 3Nb (SO4) 4.

 As a complex of these mineral derivatives with a solvent, mention may be made, for example, of the complex between NbCl4 and THF.

 The organic derivatives which can be used according to the invention are very particularly in the form of salts or complexes in which the niobium is in the oxidation state 4 or 5.

 Among the organic salts or complexes with niobium, special mention will be made of those with organic derivatives containing at least one hetero atom or an electron donor function capable of giving one or two electrons.

 By way of hetero atom of an electron donor character, mention may be made of oxygen, nitrogen, sulfur.

 By way of functions of an electron donor nature, mention may be made of carboxylic acid, sulfuric acid, phosphoric acid, amine, alcohol, thiol, ether, thioether functions.

 As preferred organic derivatives, mention will be made of niobium complexes with ligands comprising at least one free electronic doublet, preferably several, that is to say with organic derivatives called polydentates, and in particular bidentates, tridentates and tetradentates .

 As a family of preferred complexes, there may be mentioned, without being limiting, the complexes of niobium with amines, polyamines, alcohols, polyols, sugars, sugar polymers, nucleotides, thiols, amino- acids, amino alcohols, guanines, oxymes, diketones-1,3, carboxylic, phosphoric, sulfuric, carboxydi thionic, carbamadithioic acids, phenols, catechols, Schiff bases, proteins, peptides, polyfunctional derivatives containing heteroatoms such as oxygen, sulfur, nitrogen, rings containing these heteroatoms.

 These organic and complex derivatives have the advantage of being easily formed by contact of said ligand with an inorganic derivative or an organic niobium salt in the oxidation state 4 or 5 either in solution or in suspension in a solvent. Reference will be made to the synthetic examples given as illustrative examples highlighting the simplicity of formation of organic complexes and salts of niobium where the niobium is a degree of oxidation 4 or 5, useful according to the invention.

 As niobium derivative useful for the preparation of complexes or combinations useful according to the present invention, mention will be made of oxides, halides, in particular chloride, oxyhalides, sulphate, alkali metal or ammonium metallate, acetate, acetylacetonate and their derivatives as hydrate or complex form with a solvent.

 Examples of salts and complexes which can be used according to the invention include oxalate, tartrate, alcoholate, catecholate.

Among the families of complexes or association preferred according to the invention, mention will be made
- complexes or association of niobium in the oxidation state 4 or 5 with Inositol, inositol phosphate or their derivatives,
- the complexes or association of niobium with the degree of oxidation 4 or 5 with amino acids and their derivatives, in particular their derivatives in the form of amide or tertiary or secondary amine,
- complexes or association of niobium to the oxidation state 4 or 5 with organic compounds containing a cycle containing at least two nitrogen atoms.

 Examples of such organic compounds include imidazole, pyrazole, purine base, pyrimidine base derivatives or derivatives containing a polydentate macrocycle containing 6 to 30 atoms, at least 3 of which are heteroatoms.

 - complexes or association of niobium with oxidation state 4 or 5 with derivatives of dithiocarbamates.

 An important advantage of the complexes useful according to the invention is that they are generally easily formed by simple contacting of the organic ligand with the niobium derivative at the oxidation state 4 or 5.

 This reaction is most often carried out at room temperature or at a moderate temperature, generally less than 500C.

 This reaction can be carried out either in solution in water or in a solvent.

 As solvent, mention may be made of hydroalcoholic mixtures, for example mixtures containing 100 to 70% of water for 0 to 30% of alcohol.

 The alcohol used in the constitution of the hydroalcoholic medium is advantageously chosen from linear or branched C1-C4 alcohols, advantageously ethyl alcohol.

 The reaction can also be carried out in suspension in an organic agent. By way of example, mention will be made of THF, DMF and dichloromethane.

 The organometallic complexes described above are used for the preparation of medicaments useful in the treatment or prevention of diseases such as diabetes, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia as well as complications associated with these pathologies.

 As mentioned above, niobium is found in oxidation state 4 or 5 in the mineral or organometallic derivatives useful according to the invention.

 According to a particularly advantageous variant, it is found there in the oxidation state 5.

 Furthermore, the Applicant has found, quite surprisingly, that the use of a mixture of a mineral derivative or of a niobium complex useful according to the invention with a mineral derivative or a complex of a derivative of vanadium in oxidation state 4 or 5 made it possible to obtain antidiabetic effects at doses lower than what one might expect taking into account the activity of each of the two derivatives or complexes. The invention therefore also relates to the use of a mixture of a niobium salt or complex with degree of oxidation 4 or 5 and of a vanadium salt or complex with degree of oxidation 4 or 5, as active material for the manufacture of a medicament useful for the treatment or prevention of disorders of the metabolism of carbohydrates and / or of lipids, in particular of diabetes.

 As a synergistic mixture, mention may be made, for example, of the mixture of the niobium and vanadium complexes with proline, more particularly that of a mixture of a proline complex with vanadium 4 and a proline complex with niobium 5.

 The present invention therefore relates to the use in pharmaceutical compositions of the complexes described above or of the mixture of their two constituents not yet complexed but capable of complexing in the organism after administration of the pharmaceutical composition.

 The pharmaceutical compositions containing the complexes or associations of the invention may be in different forms. The niobium derivatives, in the form of salts, complexes or mixtures of the invention will be incorporated into a pharmaceutically acceptable excipient, vehicle, or support.

 As pharmaceutically acceptable excipients, vehicles or supports, any excipient, vehicle or support well known to those skilled in the art can be used. Mention may be made, for example, and without limitation of lactose, corn starch, glucose, gum arabic, stearic acid or magnesium stearate, dextrin, mannitol, talc or an oil of natural origin rich in essential unsaturated fatty acids, etc. In particular, if this proves to be necessary, it is possible to use other additives well known to those skilled in the art such as stabilizers, desiccants, binders, pH buffers, etc.

 An advantage of the complexes described above is that they can be used directly without prior purification other than the removal of the solvent, in particular when it is an organic solvent.

 The pharmaceutical compositions can be administered in various ways, in particular by the oral, mucous (oral, nasal, ocular) route. They can also be in injectable form and intended for subcutaneous, intramuscular or intravenous injection.

 They can also be used in local application, for example in the form of patches.

 The organometallic associations advantageously represent from 5 to 80% by weight relative to the total weight of the pharmaceutical preparation, and are found incorporated in an acceptable excipient, vehicle or pharmaceutical support compatible with the mode of administration envisaged.

 The pharmaceutical compositions according to the invention when they are intended for oral administration advantageously contain from 10 to 5000 nanomoles of metal derivative per dose.

 The compositions in the form of injectable formulations advantageously contain from 20 to 10,000 nanomoles of metal derivative per injectable dose of 1 to 10 ml.

 The compositions intended for local application, in particular in the form of a patch, advantageously contain from 0.1 to 100 micromoles of metal derivative per applicable dose.

 The following examples are given purely by way of illustration and in no way limit the invention. They demonstrate the ease of preparation of the salts and complexes useful according to the invention, the use of the different niobium derivatives for preparing pharmaceutical compositions and the effectiveness of the active material.

Example 1
Preparation of niobium oxalate:
A concentrated aqueous solution of Nb205 is prepared, to which a saturated and hot solution of sodium monooxalate NaHC204 is added. On cooling it precipitates sodium monooxalate which is filtered. This solution is then left under the extractor hood until about two thirds of the water has evaporated. The colorless crystals which appear are filtered, washed with alcohol and dried under vacuum.

Example 2
Preparation of niobium tartrate
An aqueous solution of Nb205 is prepared to which a solution of ammonium monotartrate C 4H9O6N is added. This solution is then heated to 850C for 2 h while allowing the water to evaporate. When cooling by a water-ice bath nothing precipitates. The solution is then concentrated under vacuum to approximately 10 ml, and precipitated by addition of alcohol. The precipitate is filtered and washed with alcohol, then dried under vacuum.

Example 3
Preparation of a niobium alcoholate:
A solution of 5 mmol of NbCl: THF is poured into THF
4xane, of 20 mmol anhydrous under nitrogen, on a suspension in hexane, of 20 mmol of Lithium alcoholate of phytol, alcoholate prepared in situ pre
o yield by addition to OC of 20 mmol of nBuLi on 20 mmol of phytol. This solution is then heated to 450C for 2 h. The solvents are then evaporated under vacuum and the product dried at 400C with a vane pump.

Example 4
Preparation of a mixed complex of niobium ethanolate and prolinol:
A solution of 2 mmol of Nb (OEt) 5 in toluene is prepared to which a solution of 4 mmol of 2pyrrolidine methanol in toluene is added. This solution is then heated to 850C for 5 h. When cooling by a water-ice bath nothing precipitates. The solution is then evaporated under vacuum at this temperature.

Example 5
Preparation of a niobium catecholate
A solution of 2.5 mmol of NbCl5 in anhydrous toluene is heated to reflux under nitrogen, then 20 mmol of recrystallized catechol are added thereto. This solution is then heated to 850C for 16 h. While cooling it precipitates red needles. The whole is placed in the cold (+ 60C) for 48 h, then the precipitate is filtered, washed with hexane, then dried under vacuum.

Example 6
Preparation of a niobium and pyridine complex
An excess of pyridine is added to a solution of 5 mmol of NbCl4: THF in absolute ethanol. The mixture is left stirring overnight, then it is cooled to 0 ° C. and the red precipitate which forms is filtered. This precipitate is dried under vacuum at 300C.

Example 7
Preparation of a niobium derivative with diethylcarbamadi thionic acid:
1.25 mmol NbCl4: THF is reacted with 5 mmol of
Et2NCS2Na in 35 ml of acetonitrile for 2 h, then the solvent is evaporated in vacuo. The dark purple compound obtained is dried at SO0C under vacuum of the vane pump.

Example 8
Preparation of a niobium and diethylamine complex
4 equivalents of diethylamine are added to an aqueous solution of Nib 205 (freshly prepared). The mixture is left stirring for 4 h, then the water is evaporated at 700C on a rotary evaporator.

Example 9
Preparation of a niobium and oleylamine complex
2 equivalents of an alcoholic oleylamine solution are added to an aqueous solution of Nb205. We leave under agitation
o tion overnight, then evaporate the water at 45 C under vacuum.

Example 10
Preparation of a niobium derivative with an aminodiol
2 equivalents of an aqueous solution of 2,3-hydroxypropylamine are reacted with an aqueous solution of Nb205. We
o reflux overnight, then evaporate the water at 60 C under vacuum from the water pump. The compound obtained is then dried at 55 ° C. under vacuum of the vane pump.

Example 11
Preparation of a proline complex with niobium 5
In an anhydrous TKF solution and under nitrogen, 25 millimoles of L-proline (2.875 g) are suspended, then 5 millimoles of NbCl5 (1.35 g) are added all at once. The resulting yellow solution becomes darker and darker very quickly (orange, then red, then brown, then black with blue reflections) as the proline dissolves. Then it discolors very quickly until it becomes very slightly yellow. A little methanol is added, then the solvents are evaporated under vacuum (water pump)
o by heating to 40 C. The vacuum drying of the vane pump is completed at 750C. The result is a very thin light yellow film on the flask, which is practically unstuck. To recover the product, it is dissolved in 50 ml of water and transferred to a bottle, where it solidifies into a kind of white gelatin.

Example 12
Preparation of a proline salt with niobium 4:
In an anhydrous THF solution and under nitrogen, 20 millimoles of L-proline (2.3 g) are suspended, then 5 millimoles of the complex of niobium chloride with the
THF or NbCl4: THF (1.895 g). The resulting red-ocher solution quickly becomes darker (brown-black with yellow-green reflections). A little methanol is added, then the solvents are evaporated under vacuum (water pump) while heating to 40 C. This results in a very hygroscopic dark gummy product.

Example 13
Preparation of pyrazole complexes with niobium 5:
2.5 mmol (0.675 g) of NbCl5 dissolved in 15 ml of THF is added to a solution of anhydrous THF under nitrogen containing 0.851 g (12.5 mmol) of pyrazole. The mixture obtained turns dark yellow very quickly. After 2 h of stirring, the solvent is evaporated, then
o dry with a vane pump at 45 C for 3 h.

Example 14
Preparation of cytosine complexes with niobium 5:
5 mmol of cytosine (0.556 g) are suspended in 20 ml of anhydrous THF under nitrogen, then 15 ml of a THF solution containing 2.5 mmol of NbCl5 (0.675 g) is added. All the white precipitate in suspension gradually becomes yellow.

 After 3 h, methanol is added, the mixture then becomes a white gel.

Example 15
Preparation of 1/1 complexes of inositol hexaphosphate (physical acid) and niobium
In 2.5 ml of anhydrous THF in which 2.5 mmol of the sodium salt of phytic acid is suspended, 2.5 mmol of niobium pentachloride Nb (Cl) 5 (0.675 g) dissolved in 15 ml of THF. The yellow solution turns white and a white powder remains in suspension. After 2 h of stirring, 15 ml of MeOH are added. Then the solvents are evaporated on a rotary evaporator.

Example 16
Formulation in any pharmaceutically acceptable diluent or excipient a) Example of composition for oral administration
A metal complex prepared according to any one of Examples 1 to 15 is mixed in a mill, in an amount of 10 to 5000 nanomoles of metal (preferably from 20 to 250 nanomoles), with a sugar polymer, for example dextran or cellulose, with zinc stereate, in sufficient amounts to make a 100 milligram tablet, which is then coated with gum arabic and sorbitan monosterate. Advantageously, gastro-resistant gel capsules based on gelatin, titanium dioxide and cellulose ester can be prepared.

b) Example of composition for administration by injection
A metal complex prepared according to any one of Examples 1 to 15 and which is soluble in water, is dissolved in an amount of 20 to 10,000 nanomoles of metal (preferably from 50 to 500 nanomoles), in 1 to 10 milliliters of sterile deionized water (preferably 2 to 4 milliliters), then it is adjusted in pH and in mineral salts so as to be as close as possible to physiological saline (pH 7.4 and 9 g / l), by base acids, or mineral salts made up of elements found in the blood, preferably H +, HO, Na +, Cl c) Example of composition for local application:
A metal complex prepared according to any one of the preceding examples 1 to 15 is emulsified, micronized or suspended in an amount of 0.1 to 100 micromoles of metal (preferably from 1 to 20 micromoles), in a water emulsion, glycerol, mono-, diet triglycerides of fatty acids, and fatty alcohols.

Example 17
Determination of a hypoglycemic effect:
The injection of 60 mg / kg of streptozotocin intravenously in the rat causes, within 24 hours of the injection, the induction of a stable diabetes mellitus, irreversible and insulin sensitive. Subsequent hyperglycemia can be reduced by the administration of substances with hypoglycaemic properties.

a) Protocol
The tests were carried out on male rats of the Wistar strain (6 per batch), coming from the breeding center of the
Faculty of Pharmacy of Montpellier.

 The animals are kept under observation for 4 days before the start of the tests. At the start of the test, the animals weigh on average 180 g. During the observation period, the animals, divided into cages of 3, receive food and drinking water ad libitum and are subjected to a temperature between 21 and 230C and to a day / dark cycle of 12 h.

 In all trials, diabetes was induced by injection of streptozotocin SIGMA in citrate buffer at pH 4.5.

 Animals with an average weight of 180 g are anesthetized with ether. An intravenous injection of streptozotocin is performed in the vein of the penis; a control glycemia is carried out 72 h after the administration of streptozotocin; only animals with a blood sugar level greater than or equal to 3 g / l (on average 3.8 g / l) are selected and subjected to treatment with the test substance.

The niobium derivatives and complexes were administered under the following injection conditions:
doses corresponding to 120 micromoles of niobium were administered the first two days and 60 micromoles the following 13 days.

 The glycemia control is carried out in the morning at 9 a.m., the time of the day when the glycemia of the diabetic control or treated rats, subjected to large variations during the day, is the highest. Diabetic rats receive only the excipient (physiological saline) and serve as diabetic controls; finally, "white control" rats of the same weight, which have not received an injection of streptozotocin are kept in order to compare the consumption of water and food.

b) Results
The daily glycemic control did not allow us to highlight the hypoglycemic effect during the first two days of treatment. A significant and significant drop in blood sugar compared to that of control rats appears from the following days and is maintained in most cases even after treatment is stopped. This is accompanied by an equally significant reduction in polyphagia and polydipsia, which they manifest from the first days. Food and water consumption cover values tending to approach those of non-diabetic control rats.

 The consumption figures for water, food and the evolution of the glycemia of rats treated with different niobium derivatives are given in the attached figures.

 The results are represented, for each derivative, in the form of a bar diagram; the black bar corresponding to the results obtained with the diabetic controls and the hatched bar corresponding to the results obtained with the rats treated with derivatives useful according to the invention.

 FIGS. 1a, 1b and 1c respectively represent the variations in consumption of water, food and the variations in the blood sugar level over time for a batch of diabetic rats treated with niobium sulphate corresponding to the formula (NH4) 3Nb (S04) 4 and referenced "sulfate" in the figures, in comparison with the results obtained for a batch of untreated diabetic rats.

 FIGS. 2a, 2b and 2c respectively represent the variations in consumption of water, food and the variations in the blood sugar level over time for a batch of diabetic rats treated with the product of Example 4 in comparison with the results. obtained for a batch of untreated diabetic rats.

 FIGS. 3a, 3b and 3c respectively represent the variations in consumption of water, food and the variations in the blood sugar level over time for a batch of diabetic rats treated with the product of Example 7 in comparison with the results. obtained for a batch of untreated diabetic rats.

 FIGS. 4a, 4b and 4c respectively represent the variations in consumption of water, food and the variations in the blood sugar level over time for a batch of diabetic rats treated with the product of Example 1 in comparison with your results. obtained for a batch of untreated diabetic rats.

 FIGS. 5a, 5b and 5c respectively represent the variations in consumption of water, food and the variations in the blood sugar level over time for a batch of diabetic rats treated with the product of Example 13 in comparison with the results. obtained for a batch of untreated diabetic rats.

 FIGS. 6a, 6b and 6c respectively represent the variations in consumption of water, food and the variations in the blood sugar level over time for a batch of diabetic rats treated with the product of Example 14 in comparison with the results. obtained for a batch of untreated diabetic rats.

 FIGS. 7a, 7b and 7c respectively represent the variations in consumption of water, food and the variations in the blood sugar level over time for a batch of diabetic rats treated with the product of example 15 in comparison with the results obtained for a batch of untreated diabetic rats.

 Note that the values given in these figures are averages obtained for the whole of a lot.

 As in some cases, one or two animals in the batch are not corrected, these means are slightly higher than the corresponding parameters of healthy subjects.

 There has been a marked reduction in the consumption of water and food accompanied by a significant drop in blood sugar.

 In addition, the weight development as well as that of the food consumption / weight gain ratio clearly show a hypoglycemic effect that no current treatment for diabetes provides since, in particular, it is prolonged in the majority of cases after stopping the treatment.

 Furthermore, it should be noted that the observation of subjective parameters, such as the appearance of the animals and their behavior, also shows the positive effect of the treatment.

 Measuring cholesterol and triglyceride levels also shows improvement.

 Like humans, diabetic rats develop metabolic disorders (hypercholesterolemia, hyperlipidemia, hypertriglyceridemia ...) as well as pathologies such as hypertension, arteriosclerosis, heart failure, peripheral ischemia, or even eye pathologies progressing to blindness .

 It has been shown that in treated rats, which have become normoglycemic, the disorders and complications described above do not appear.

Claims (13)

 1. Use of niobium derivatives in the oxidation state 4 or 5 as active ingredient for the manufacture of medicaments useful in the treatment and / or prevention of disorders of the metabolism of carbohydrates and / or of lipids.  2. Use according to claim 1, characterized in that the niobium derivative in the oxidation state 4 or 5 is an inorganic derivative.  3. Use according to claim 2, characterized in that said mineral derivative is soluble in water.  4. Use according to claim 3, characterized in that the water-soluble mineral derivative leads to solutions of pH between 3 and 9, preferably close to 7.  5. Use according to claim 1, characterized in that the niobium is in the form of an organic derivative where the niobium is in the oxidation state 4 or 5, said derivative being an organic salt or an organic complex.  6. Use according to claim 5, characterized in that said organic derivative contains at least one hetero atom or an electro-donor function.  7. Use according to claim 5 or 6, characterized in that the organic derivative is a complex with a ligand carrying at least one free electronic doublet.  8. Use according to one of claims 5 to 7, characterized in that the niobium derivative is a salt or a complex with an organic product belonging to the family of amines, polyamines, alcohols, polyols, sugars, sugar polymers, nucleotides, thiols, amino acids, amino alcohols, guanines, oxymes, 1,3-diketones, carboxylic, phosphoric, sulfuric, carboxydithioic, carbamadithioic, phenols, catechols, Schiff bases, proteins, peptides, polyfunctional derivatives containing hetero -atoms such as oxygen, sulfur, nitrogen, rings containing these hetero atoms.  9. Use according to one of claims 1 to 8, characterized in that the niobium derivative is mixed with a salt or complex of vanadium where the vanadium is at the oxidation state 4 or 5.  10. Use of a mixture of niobium complexes at oxidation state 4 or 5 with proline and vanadium complexes at oxidation state 4 or 5 with proline as active ingredient for the manufacture of a medicament useful for treatment of diabetes.  11. Use according to one of claims 1 to 10, characterized in that said medicament is useful for the treatment of diabetes  12. Use according to one of claims 1 to 10, characterized in that said medicament is useful for the treatment or prevention of diabetes, hypercholesterolemia, hyperlipidemia or hypertriglyceridemia of the complications associated with these pathologies .  13. Use according to one of claims 1 to 12 characterized in that the niobium is at the oxidation state 5.